The objective of this proposal is first to define the importance of glucose metabolism in hypoxic cells following hyperthermia; and second, to find a means to specifically enhance killing of the radioresistant hypoxic cells by heat and radiation. Findings from our recent cell culture studies have provided us with some important clues. Since HeLa cells under glucose and oxygen deprivation become selectively sensitive to heat, we plan to study the intermediary glucose metabolism to define the specific steps of carbon substrate utilization that is related to the thermal sensitization. Studies will be carried out with HeLa cells to determine the importance of glycolysis, gluconeogenesis and hexose monophosphate shunt pathway by the use of specific metabolic inhibitors. Subsequent studies will be directed to determine a set of cultural conditions which will effectively reduce oxygen enhancement ratio (OER). Specifically, the effect of pH and various metabolic inhibitors of glucose metabolism will be determined. The significance of the present studies lies in two areas. First, identification of any method and specific conditions to reduce the radioresistance of hypoxic cells will contribute toward better application of combination hyperthermia and radiation therapy. Second, perhaps equally as important, the data might provide an important clue toward identification of the principal site of hyperthermic damage in cancer cells.